Mar 27, 2018

A polymorphism in the lysyl oxidase propeptide domain accelerates carcinogen-induced cancer

Carcinogenesis
Ana de la CuevaKathrin H Kirsch

Abstract

The propeptide (LOX-PP) domain of the lysyl oxidase proenzyme was shown to inhibit the transformed phenotype of breast, lung and pancreatic cells in culture and the formation of Her2/neu-driven breast cancer in a xenograft model. A single nucleotide polymorphism (SNP, rs1800449) positioned in a highly conserved region of LOX-PP results in an Arg158Gln substitution (humans). This arginine (Arg)→glutamine (Gln) substitution profoundly impaired the ability of LOX-PP to inhibit the invasive phenotype and xenograft tumor formation. To study the effect of the SNP in vivo, here we established a knock in (KI) mouse line (LOX-PPGln mice) expressing an Arg152Gln substitution corresponding to the human Arg158Gln polymorphism. Breast cancer was induced in wild-type (WT) and LOX-PPGln female mice beginning at 6 weeks of age by treatment with 7,12-dimethylbenz(a)anthracene (DMBA) in combination with progesterone. Time course analysis of tumor development demonstrated earlier tumor onset and shorter overall survival in LOX-PPGln versus WT mice. To further compare the tumor burden in WT and LOX-PPGln mice, inguinal mammary glands from both groups of mice were examined for microscopic lesion formation. LOX-PPGln glands contained more lesions (9...Continue Reading

  • References41
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References

  • References41
  • Citations1

Citations

Mentioned in this Paper

Biological Markers
Gene Polymorphism
Tumor Promoters
ErbB-2 Receptor
Study
In Vivo
Tumor Suppressor Genes
9,10-Dimethyl-1,2-benzanthracene
Lung
Mammary Gland

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